Targeting of OSBP-related protein 3 (ORP3) to endoplasmic reticulum and plasma membrane is controlled by multiple determinants

Lehto, Markku; Hynynen, Riikka; Karjalainen, Katja; Kuismanen, Esa; Hyvärinen, Kati; Olkkonen, Vesa M.

doi:10.1016/j.yexcr.2005.08.003

Cited by 77 publications

(55 citation statements)

References 49 publications

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“…As previously reported for other cell lines (14,15), ORP1L localized to late endo/lysosomal structures (see supplementary Fig. IA-C) and ORP3 to the ER and the cytosol (see supplementary Fig.…”

Section: Orp2 Localizes To the Surface Of Intracellular Ldssupporting

confidence: 86%

“…The addition of oxysterols to cells has been shown to affect the localization of OSBP (17) and an ORP3:OSBP chimera (15). We wanted to test if the same applies to ORP2.…”

Section: (R)hydroxycholesterol Inhibits the Ld Association Of Orp2mentioning

confidence: 99%

“…to late endosomes (14), ORP3, -6, and -7 to the plasma membrane (15), and OSBP (16,17) and ORP9 (18) to the Golgi complex. OSBP is targeted to Golgi complex in response to treatment of cells with its high-affinity ligand 25-hydroxycholesterol (25OHC).…”

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confidence: 99%

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OSBP-related protein 2 is a sterol receptor on lipid droplets that regulates the metabolism of neutral lipids

Hynynen

Suchanek

Spandl

et al. 2009

Journal of Lipid Research

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122

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Oxysterol binding protein-related protein 2 (ORP2) is a member of the oxysterol binding protein family, previously shown to bind 25-hydroxycholesterol and implicated in cellular cholesterol metabolism. We show here that ORP2 also binds 22(R)-hydroxycholesterol [22(R)OHC], 7-ketocholesterol, and cholesterol, with 22(R)OHC being the highest affinity ligand of ORP2 (K d 1.4 3 10 28 M). We report the localization of ORP2 on cytoplasmic lipid droplets (LDs) and its function in neutral lipid metabolism using the human A431 cell line as a model. The ORP2 LD association depends on sterol binding: Treatment with 5 mM 22(R)OHC inhibits the LD association, while a mutant defective in sterol binding is constitutively LD bound. Silencing of ORP2 using RNA interference slows down cellular triglyceride hydrolysis. Furthermore, ORP2 silencing increases the amount of (5), and inhibit the processing of sterol regulatory element binding proteins (SREBPs) via binding to the Insig proteins, which retain SREBP/SCAP complexes in the endoplasmic reticulum (ER) (6). The cytosolic oxysterol receptor, oxysterol binding protein (OSBP), was identified in the 1980s (7). Families of OSBP-related proteins (ORPs) have recently been identified in practically all eukaryotic organisms studied (8). Most of the information on the ORP proteins has been obtained using yeast (Saccharomyces cerevisiae) or mammalian cells. The yeast ORPs (Osh proteins) are suggested to play major roles in the intracellular transport of sterols (9), in vesicle budding from the Golgi apparatus (10, 11), and in the establishment of cell polarity (12, 13), while mammalian ORPs have been suggested to participate in the regulation of lipid metabolism, vesicle transport, and cellular signaling (8).All ORPs contain in their C-terminal part a structure designated OSBP-related domain (ORD), which is homologous to the oxysterol binding domain of OSBP (8). In addition to the ORD, most ORPs contain an N-terminal region involved in their subcellular targeting. The N-terminal extensions containing a pleckstrin homology domain target ORP1L Abbreviations: 22(R)OHC, 22(R)-hydroxycholesterol; 25OHC, 25-hydroxycholesterol; CE, cholesteryl ester; CHO, Chinese hamster ovary; ER, endoplasmic reticulum; FCS, fetal calf serum; FFAT, two phenylalanines in an acidic tract; GST, glutathione S-transferase; LD, lipid droplet; mab, monoclonal mouse antibody; mbCD, methyl-b-cyclodextrin; ORD, oxysterol binding protein-related domain; ORP, oxysterol binding protein-related protein; OSBP, oxysterol binding protein; siRNA, short interfering RNA; SREBP, sterol regulatory element binding protein; TG, triglyceride.

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Section: Orp2 Localizes To the Surface Of Intracellular Ldssupporting

confidence: 86%

“…The addition of oxysterols to cells has been shown to affect the localization of OSBP (17) and an ORP3:OSBP chimera (15). We wanted to test if the same applies to ORP2.…”

Section: (R)hydroxycholesterol Inhibits the Ld Association Of Orp2mentioning

confidence: 99%

See 1 more Smart Citation

OSBP-related protein 2 is a sterol receptor on lipid droplets that regulates the metabolism of neutral lipids

Hynynen

Suchanek

Spandl

et al. 2009

Journal of Lipid Research

Self Cite

122

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“…Recent studies suggest that OSBPs act as sterol transfer and/or sensor proteins that may also play important roles in cell signaling (39,40). OSBPL3, a member of subfamily III, contains a conserved sterol-binding OSBP homology domain (OHD) as well as a phosphatidylinositol lipid species-binding pleckstrin homology (PH) domain and two 2-phenylalanines in an acidic tract (FFAT) domains that bind to the vesicle-associated membrane protein-associated (VAMP-associated) protein (VAP) (39,41,42). Recently, it has been shown that this last interaction can activate R-RAS, thus reorganizing the actin cytoskeleton and affecting cell polarity and cell-cell adhesion (43).…”

Section: Discussionmentioning

confidence: 99%

Impaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver disease

Stein¹,

Lemos²,

Xu³

et al. 2017

Journal of Clinical Investigation

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“…We conclude that VAPB-P56S aggregates include tubular membrane structures, which most likely originate from the ER. Their appearance was clearly distinct from the organized smooth ER (OSER) (Snapp et al, 2003) induced by the coexpression of VAPs and FFAT-motif proteins (Amarilio et al, 2005;Lehto et al, 2005).…”

Section: P56s Mutant Vapb Forms Protein Aggregates Containing Er Tubulesmentioning

confidence: 97%

Motor Neuron Disease-Associated Mutant Vesicle-Associated Membrane Protein-Associated Protein (VAP) B Recruits Wild-Type VAPs into Endoplasmic Reticulum-Derived Tubular Aggregates

Teuling¹,

Ahmed²,

Haasdijk³

et al. 2007

J. Neurosci.

213

310

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The vesicle-associated membrane protein-associated proteins (VAPs) VAPA and VAPB interact with lipid-binding proteins carrying a short motif containing two phenylalanines in an acidic tract (FFAT motif) and targets them to the cytosolic surface of the endoplasmic reticulum (ER). A genetic mutation (P56S) in the conserved major sperm protein homology domain of VAPB has been linked to motorneuron degeneration in affected amyotrophic lateral sclerosis (ALS) patients. We report that in the CNS, VAPB is abundant in motor neurons and that the P56S substitution causes aggregation of mutant VAPB in immobile tubular ER clusters, perturbs FFAT-motif binding, and traps endogenous VAP in mutant aggregates. Expression of mutant VAPB or reduction of VAP by short hairpin RNA in primary neurons causes Golgi dispersion and cell death. VAPA and VAPB are reduced in human ALS patients and superoxide dismutase 1 (SOD1)-ALS-transgenic mice, suggesting that VAP family proteins may be involved in the pathogenesis of sporadic and SOD1-linked ALS. Our data support a model in which reduced levels of VAP family proteins result in decreased ER anchoring of lipid-binding proteins and cause motor neuron degeneration.

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Targeting of OSBP-related protein 3 (ORP3) to endoplasmic reticulum and plasma membrane is controlled by multiple determinants

Cited by 77 publications

References 49 publications

OSBP-related protein 2 is a sterol receptor on lipid droplets that regulates the metabolism of neutral lipids

OSBP-related protein 2 is a sterol receptor on lipid droplets that regulates the metabolism of neutral lipids

Impaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver disease

Motor Neuron Disease-Associated Mutant Vesicle-Associated Membrane Protein-Associated Protein (VAP) B Recruits Wild-Type VAPs into Endoplasmic Reticulum-Derived Tubular Aggregates

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